Delivery of opioids through an inhalation route

ABSTRACT

The present invention relates to the delivery of opioids through an inhalation route. Specifically, it relates to aerosols containing opioids that are used in inhalation therapy. In a method aspect of the present invention, an opioid is delivered to a patient through an inhalation route. The method comprises: a) heating a composition, wherein the composition comprises an opioid, to form a vapor; and, b) allowing the vapor to cool, thereby forming a condensation aerosol comprising particles with less than 5% opioid degradation products. In a kit aspect of the present invention, a kit for delivering an opioid through an inhalation route is provided which comprises: a) a thin coating of an opioid composition and b) a device for dispensing said thin coating as a condensation aerosol.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.10/153,839 entitled “Delivery of Opioids Through an Inhalation Route,”filed May 21, 2002, now U.S. Pat. No. 6,776,978 Rabinowitz andZaffaroni, which claims priority to U.S. provisional application Ser.No. 60/294,203 entitled “Thermal Vapor Delivery of Drugs,” filed May 24,2001, Rabinowitz and Zaffaroni, and to U.S. provisional application Ser.No. 60/317,479 entitled “Aerosol Drug Delivery,” filed Sep. 5, 2001,Rabinowitz and Zaffaroni, the entire disclosures of which are herebyincorporated by reference.

FIELD OF THE INVENTION

The present invention relates to the delivery of opioids through aninhalation route. Specifically, it relates to aerosols containingopioids that are used in inhalation therapy.

BACKGROUND OF THE INVENTION

There are a number of currently marketed opioid compositions. Thecompositions contain at least one active ingredient that provides forobserved therapeutic effects. Among the active ingredients given in suchopioid compositions are morphine, codeine, naltrexone, buprenorphine,fentanyl, nalbuphine, naloxone, butorphanol, hydromorphone, oxycodone,meperidine, methadone, pentazocine, remifentanil, and sufentanil.

It is desirable to provide a new route of administration for the opioidsthat rapidly produces peak plasma concentrations of the compounds. Theprovision of such a route is an object of the present invention.

SUMMARY OF THE INVENTION

The present invention relates to the delivery of opioids through aninhalation route. Specifically, it relates to aerosols containingopioids that are used in inhalation therapy.

In a composition aspect of the present invention, the aerosol comprisesparticles comprising at least 5 percent by weight of an opioid.Preferably, the particles comprise at least 10 percent by weight of anopioid. More preferably, the particles comprise at least 20 percent, 30percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90percent, 95 percent, 97 percent, 99 percent, 99.5 percent or 99.97percent by weight of an opioid.

Typically, the opioid is not morphine or heroin.

Typically, the aerosol has a mass of at least 1 μg. Preferably, theaerosol has a mass of at least 10 μg. More preferably, the aerosol has amass of at least 20 μg.

Typically, the particles comprise less than 10 percent by weight ofopioid degradation products. Preferably, the particles comprise lessthan 5 percent by weight of opioid degradation products. Morepreferably, the particles comprise less than 2.5, 1, 0.5, 0.1 or 0.03percent by weight of opioid degradation products.

Typically, the particles comprise less than 90 percent by weight ofwater. Preferably, the particles comprise less than 80 percent by weightof water. More preferably, the particles comprise less than 70 percent,60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10 percent,or 5 percent by weight of water.

Typically, at least 50 percent by weight of the aerosol is amorphous inform, wherein crystalline forms make up less than 50 percent by weightof the total aerosol weight, regardless of the nature of individualparticles. Preferably, at least 75 percent by weight of the aerosol isamorphous in form. More preferably, at least 90 percent by weight of theaerosol is amorphous in form.

Typically, the aerosol has an inhalable aerosol particle density greaterthan 10⁶ particles/mL. Preferably, the aerosol has an inhalable aerosolparticle density greater than 10⁷ particles/mL or 10⁸ particles/mL.

Typically, the aerosol particles have a mass median aerodynamic diameterof less than 5 microns. Preferably, the particles have a mass medianaerodynamic diameter of less than 3 microns. More preferably, theparticles have a mass median aerodynamic diameter of less than 2 or 1micron(s).

Typically, the aerosol is formed by heating a composition containing anopioid to form a vapor and subsequently allowing the vapor to condenseinto an aerosol.

In another composition aspect of the present invention, the aerosolcomprises particles comprising at least 5 percent by weight of morphine,codeine, naltrexone, buprenorphine, fentanyl, nalbuphine, naloxone,butorphanol, hydromorphone, oxycodone, meperidine, methadone,pentazocine, remifentanil, or sufentanil. Preferably, the particlescomprise at least 10 percent by weight of morphine, codeine, naltrexone,buprenorphine, fentanyl, nalbuphine, naloxone, butorphanol,hydromorphone, oxycodone, meperidine, methadone, pentazocine,remifentanil, or sufentanil. More preferably, the particles comprise atleast 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent,99.5 percent or 99.97 percent by weight of morphine, codeine,naltrexone, buprenorphine, fentanyl, nalbuphine, naloxone, butorphanol,hydromorphone, oxycodone, meperidine, methadone, pentazocine,remifentanil, or sufentanil.

Typically, the aerosol has a mass of at least 1 μg. Preferably, theaerosol has a mass of at least 10 μg. More preferably, the aerosol has amass of at least 20 μg.

Typically, the particles comprise less than 10 percent by weight ofmorphine, codeine, naltrexone, buprenorphine, fentanyl, nalbuphine,naloxone, butorphanol, hydromorphone, oxycodone, meperidine, methadone,pentazocine, remifentanil, or sufentanil degradation products.Preferably, the particles comprise less than 5 percent by weight ofmorphine, codeine, naltrexone, buprenorphine, fentanyl, nalbuphine,naloxone, butorphanol, hydromorphone, oxycodone, meperidine, methadone,pentazocine, remifentanil, or sufentanil degradation products. Morepreferably, the particles comprise less than 2.5, 1, 0.5, 0.1 or 0.03percent by weight of morphine, codeine, naltrexone, buprenorphine,fentanyl, nalbuphine, naloxone, butorphanol, hydromorphone, oxycodone,meperidine, methadone, pentazocine, remifentanil, or sufentanildegradation products.

Typically, the particles comprise less than 90 percent by weight ofwater. Preferably, the particles comprise less than 80 percent by weightof water. More preferably, the particles comprise less than 70 percent,60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10 percent,or 5 percent by weight of water.

Typically, at least 50 percent by weight of the aerosol is amorphous inform, wherein crystalline forms make up less than 50 percent by weightof the total aerosol weight, regardless of the nature of individualparticles. Preferably, at least 75 percent by weight of the aerosol isamorphous in form. More preferably, at least 90 percent by weight of theaerosol is amorphous in form.

Typically, where the aerosol comprises morphine, the aerosol has aninhalable aerosol drug mass density of between 5 mg/L and 25 mg/L.Preferably, the aerosol has an inhalable aerosol drug mass density ofbetween 7.5 mg/L and 22.5 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 10 mg/L and 20 mg/L.

Typically, where the aerosol comprises codeine, the aerosol has aninhalable aerosol drug mass density of between 5 mg/L and 25 mg/L.Preferably, the aerosol has an inhalable aerosol drug mass density ofbetween 7.5 mg/L and 22.5 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 10 mg/L and 20 mg/L.

Typically, where the aerosol comprises naltrexone, the aerosol has aninhalable aerosol drug mass density of between 15 mg/L and 35 mg/L.Preferably, the aerosol has an inhalable aerosol drug mass density ofbetween 17.5 mg/L and 32.5 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 20 mg/L and 30 mg/L.

Typically, where the aerosol comprises buprenorphine, the aerosol has aninhalable aerosol drug mass density of between 0.1 mg/L and 1 mg/L.Preferably, the aerosol has an inhalable aerosol drug mass density ofbetween 0.15 mg/L and 0.8 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 0.2 mg/L and 0.6 mg/L.

Typically, where the aerosol comprises fentanyl, the aerosol has aninhalable aerosol drug mass density of between 0.01 mg/L and 0.8 mg/L.Preferably, the aerosol has an inhalable aerosol drug mass density ofbetween 0.02 mg/L and 0.6 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 0.3 mg/L and 0.4 mg/L.

Typically, where the aerosol comprises nalbuphine, the aerosol has aninhalable aerosol drug mass density of between 1 mg/L and 30 mg/L.Preferably, the aerosol has an inhalable aerosol drug mass density ofbetween 2 mg/L and 27.5 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 2 mg/L and 25 mg/L.

Typically, where the aerosol comprises naloxone, the aerosol has aninhalable aerosol drug mass density of between 0.05 mg/L and 3.5 mg/L.Preferably, the aerosol has an inhalable aerosol drug mass density ofbetween 0.1 mg/L and 3 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 0.2 mg/L and 2.5 mg/L.

Typically, where the aerosol comprises butorphanol, the aerosol has aninhalable aerosol drug mass density of between 0.1 mg/L and 3 mg/L.Preferably, the aerosol has an inhalable aerosol drug mass density ofbetween 0.15 mg/L and 2.75 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 0.2 mg/L and 2.5 mg/L.

Typically, where the aerosol comprises hydromorphone, the aerosol has aninhalable aerosol drug mass density of between 0.1 mg/L and 10 mg/L.Preferably, the aerosol has an inhalable aerosol drug mass density ofbetween 0.2 mg/L and 7.5 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 0.4 mg/L and 5 mg/L.

Typically, where the aerosol comprises oxycodone, the aerosol has aninhalable aerosol drug mass density of between 0.5 mg/L and 10 mg/L.Preferably, the aerosol has an inhalable aerosol drug mass density ofbetween 0.75 mg/L and 0.8 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 1 mg/L and 0.6 mg/L.

Typically, where the aerosol comprises meperidine, the aerosol has aninhalable aerosol drug mass density of between 5 mg/L and 100 mg/L.Preferably, the aerosol has an inhalable aerosol drug mass density ofbetween 7.5 mg/L and 80 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 10 mg/L and 60 mg/L.

Typically, where the aerosol comprises methadone, the aerosol has aninhalable aerosol drug mass density of between 0.25 mg/L and 20 mg/L.Preferably, the aerosol has an inhalable aerosol drug mass density ofbetween 0.5 mg/L and 17.5 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 0.75 mg/L and 15 mg/L.

Typically, where the aerosol comprises pentazocine, the aerosol has aninhalable aerosol drug mass density of between 3 mg/L and 50 mg/L.Preferably, the aerosol has an inhalable aerosol drug mass density ofbetween 4 mg/L and 45 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 5 mg/L and 40 mg/L.

Typically, the aerosol has an inhalable aerosol particle density greaterthan 10⁶ particles/mL. Preferably, the aerosol has an inhalable aerosolparticle density greater than 10⁷ particles/mL or 10⁸ particles/mL.

Typically, the aerosol particles have a mass median aerodynamic diameterof less than 5 microns. Preferably, the particles have a mass medianaerodynamic diameter of less than 3 microns. More preferably, theparticles have a mass median aerodynamic diameter of less than 2 or 1micron(s). In certain embodiments the particles have an MMAD of fromabout 0.2 to about 3 microns.

Typically, the aerosol is formed by heating a composition containingmorphine, codeine, naltrexone, buprenorphine, fentanyl, nalbuphine,naloxone, butorphanol, hydromorphone, oxycodone, meperidine, methadone,pentazocine, remifentanil, or sufentanil to form a vapor andsubsequently allowing the vapor to condense into an aerosol.

In a method aspect of the present invention, an opioid is delivered to amammal through an inhalation route. The method comprises: a) heating acomposition, wherein the composition comprises at least 5 percent byweight of an opioid, to form a vapor; and, b) allowing the vapor tocool, thereby forming a condensation aerosol comprising particles, whichis inhaled by the mammal. Preferably, the composition comprises at least10 percent by weight of an opioid. More preferably, the compositioncomprises at least 20 percent, 30 percent, 40 percent, 50 percent, 60percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99percent, 99.5 percent, 99.9 percent or 99.97 percent by weight of anopioid.

Typically, the opioid is not morphine or heroin.

Typically, the particles comprise at least 5 percent by weight of anopioid. Preferably, the particles comprise at least 10 percent by weightof an opioid. More preferably, the particles comprise at least 20percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent,99.9 percent or 99.97 percent by weight of an opioid.

Typically, the aerosol has a mass of at least 1 μg. Preferably, theaerosol has a mass of at least 10 μg. More preferably, the aerosol has amass of at least 20 μg.

Typically, the particles comprise less than 10 percent by weight ofopioid degradation products. Preferably, the particles comprise lessthan 5 percent by weight of opioid degradation products. Morepreferably, the particles comprise 2.5, 1, 0.5, 0.1 or 0.03 percent byweight of opioid degradation products.

Typically, the particles comprise less than 90 percent by weight ofwater. Preferably, the particles comprise less than 80 percent by weightof water. More preferably, the particles comprise less than 70 percent,60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10 percent,or 5 percent by weight of water.

Typically, at least 50 percent by weight of the aerosol is amorphous inform, wherein crystalline forms make up less than 50 percent by weightof the total aerosol weight, regardless of the nature of individualparticles. Preferably, at least 75 percent by weight of the aerosol isamorphous in form. More preferably, at least 90 percent by weight of theaerosol is amorphous in form.

Typically, the particles of the delivered condensation aerosol have amass median aerodynamic diameter of less than 5 microns. Preferably, theparticles have a mass median aerodynamic diameter of less than 3microns. More preferably, the particles have a mass median aerodynamicdiameter of less than 2 or 1 micron(s).

Typically, the delivered aerosol has an inhalable aerosol particledensity greater than 10⁶ particles/mL. Preferably, the aerosol has aninhalable aerosol particle density greater than 10⁷ particles/mL or 10⁸particles/mL.

Typically, the rate of inhalable aerosol particle formation of thedelivered condensation aerosol is greater than 10⁸ particles per second.Preferably, the aerosol is formed at a rate greater than 10⁹ inhalableparticles per second. More preferably, the aerosol is formed at a rategreater than 10¹⁰ inhalable particles per second.

Typically, the delivered condensation aerosol is formed at a rategreater than 0.5 mg/second. Preferably, the aerosol is formed at a rategreater than 0.75 mg/second. More preferably, the aerosol is formed at arate greater than 1 mg/second, 1.5 mg/second or 2 mg/second.

Typically, the delivered condensation aerosol results in a peak plasmaconcentration of an opioid in the mammal in less than 1 h. Preferably,the peak plasma concentration is reached in less than 0.5 h. Morepreferably, the peak plasma concentration is reached in less than 0.2,0.1, 0.05, 0.02, 0.01, or 0.005 h (arterial measurement).

In another method aspect of the present invention, one of morphine,codeine, naltrexone, buprenorphine, fentanyl, nalbuphine, naloxone,butorphanol, hydromorphone, oxycodone, meperidine, methadone,pentazocine, remifentanil, or sufentanil is delivered to a mammalthrough an inhalation route. The method comprises: a) heating acomposition, wherein the composition comprises at least 5 percent byweight of morphine, codeine, naltrexone, buprenorphine, fentanyl,nalbuphine, naloxone, butorphanol, hydromorphone, oxycodone, meperidine,methadone, pentazocine, remifentanil, or sufentanil, to form a vapor;and, b) allowing the vapor to cool, thereby forming a condensationaerosol comprising particles, which is inhaled by the mammal.Preferably, the composition comprises at least 10 percent by weight ofmorphine, codeine, naltrexone, buprenorphine, fentanyl, nalbuphine,naloxone, butorphanol, hydromorphone, oxycodone, meperidine, methadone,pentazocine, remifentanil, or sufentanil. More preferably, thecomposition comprises at least 20 percent, 30 percent, 40 percent, 50percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent byweight of morphine, codeine, naltrexone, buprenorphine, fentanyl,nalbuphine, naloxone, butorphanol, hydromorphone, oxycodone, meperidine,methadone, pentazocine, remifentanil, or sufentanil.

Typically, the particles comprise at least 5 percent by weight ofmorphine, codeine, naltrexone, buprenorphine, fentanyl, nalbuphine,naloxone, butorphanol, hydromorphone, oxycodone, meperidine, methadone,pentazocine, remifentanil, or sufentanil. Preferably, the particlescomprise at least 10 percent by weight of morphine, codeine, naltrexone,buprenorphine, fentanyl, nalbuphine, naloxone, butorphanol,hydromorphone, oxycodone, meperidine, methadone, pentazocine,remifentanil, or sufentanil. More preferably, the particles comprise atleast 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent,99.5 percent, 99.9 percent or 99.97 percent by weight of morphine,codeine, naltrexone, buprenorphine, fentanyl, nalbuphine, naloxone,butorphanol, hydromorphone, oxycodone, meperidine, methadone,pentazocine, remifentanil, or sufentanil.

Typically, the aerosol has a mass of at least 1 μg. Preferably, theaerosol has a mass of at least 10 μg. More preferably, the aerosol has amass of at least 20 μg.

Typically, the particles comprise less than 10 percent by weight ofmorphine, codeine, naltrexone, buprenorphine, fentanyl, nalbuphine,naloxone, butorphanol, hydromorphone, oxycodone, meperidine, methadone,pentazocine, remifentanil, or sufentanil degradation products.Preferably, the particles comprise less than 5 percent by weight ofmorphine, codeine, naltrexone, buprenorphine, fentanyl, nalbuphine,naloxone, butorphanol, hydromorphone, oxycodone, meperidine, methadone,pentazocine, remifentanil, or sufentanil degradation products. Morepreferably, the particles comprise 2.5, 1, 0.5, 0.1 or 0.03 percent byweight of morphine, codeine, naltrexone, buprenorphine, fentanyl,nalbuphine, naloxone, butorphanol, hydromorphone, oxycodone, meperidine,methadone, pentazocine, remifentanil, or sufentanil degradationproducts.

Typically, the particles comprise less than 90 percent by weight ofwater. Preferably, the particles comprise less than 80 percent by weightof water. More preferably, the particles comprise less than 70 percent,60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10 percent,or 5 percent by weight of water.

Typically, at least 50 percent by weight of the aerosol is amorphous inform, wherein crystalline forms make up less than 50 percent by weightof the total aerosol weight, regardless of the nature of individualparticles. Preferably, at least 75 percent by weight of the aerosol isamorphous in form. More preferably, at least 90 percent by weight of theaerosol is amorphous in form.

Typically, the particles of the delivered condensation aerosol have amass median aerodynamic diameter of less than 5 microns. Preferably, theparticles have a mass median aerodynamic diameter of less than 3microns. More preferably, the particles have a mass median aerodynamicdiameter of less than 2 or 1 micron(s).

Typically, where the aerosol comprises morphine, the delivered aerosolhas an inhalable aerosol drug mass density of between 5 mg/L and 25mg/L. Preferably, the aerosol has an inhalable aerosol drug mass densityof between 7.5 mg/L and 22.5 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 10 mg/L and 20 mg/L.

Typically, where the aerosol comprises codeine, the delivered aerosolhas an inhalable aerosol drug mass density of between 5 mg/L and 25mg/L. Preferably, the aerosol has an inhalable aerosol drug mass densityof between 7.5 mg/L and 22.5 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 10 mg/L and 20 mg/L.

Typically, where the aerosol comprises naltrexone, the delivered aerosolhas an inhalable aerosol drug mass density of between 15 mg/L and 35mg/L. Preferably, the aerosol has an inhalable aerosol drug mass densityof between 17.5 mg/L and 32.5 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 20 mg/L and 30 mg/L.

Typically, where the aerosol comprises buprenorphine, the deliveredaerosol has an inhalable aerosol drug mass density of between 0.1 mg/Land 1 mg/L. Preferably, the aerosol has an inhalable aerosol drug massdensity of between 0.15 mg/L and 0.8 mg/L. More preferably, the aerosolhas an inhalable aerosol drug mass density of between 0.2 mg/L and 0.6mg/L.

Typically, where the aerosol comprises fentanyl, the delivered aerosolhas an inhalable aerosol drug mass density of between 0.01 mg/L and 0.8mg/L. Preferably, the aerosol has an inhalable aerosol drug mass densityof between 0.02 mg/L and 0.6 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 0.3 mg/L and 0.4 mg/L.

Typically, where the aerosol comprises nalbuphine, the delivered aerosolhas an inhalable aerosol drug mass density of between 1 mg/L and 30mg/L. Preferably, the aerosol has an inhalable aerosol drug mass densityof between 2 mg/L and 27.5 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 2 mg/L and 25 mg/L.

Typically, where the aerosol comprises naloxone, the delivered aerosolhas an inhalable aerosol drug mass density of between 0.05 mg/L and 3.5mg/L. Preferably, the aerosol has an inhalable aerosol drug mass densityof between 0.1 mg/L and 3 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 0.2 mg/L and 2.5 mg/L.

Typically, where the aerosol comprises butorphanol, the deliveredaerosol has an inhalable aerosol drug mass density of between 0.1 mg/Land 3 mg/L. Preferably, the aerosol has an inhalable aerosol drug massdensity of between 0.15 mg/L and 2.75 mg/L. More preferably, the aerosolhas an inhalable aerosol drug mass density of between 0.2 mg/L and 2.5mg/L.

Typically, where the aerosol comprises hydromorphone, the deliveredaerosol has an inhalable aerosol drug mass density of between 0.1 mg/Land 10 mg/L. Preferably, the aerosol has an inhalable aerosol drug massdensity of between 0.2 mg/L and 7.5 mg/L. More preferably, the aerosolhas an inhalable aerosol drug mass density of between 0.4 mg/L and 5mg/L.

Typically, where the aerosol comprises oxycodone, the delivered aerosolhas an inhalable aerosol drug mass density of between 0.5 mg/L and 10mg/L. Preferably, the aerosol has an inhalable aerosol drug mass densityof between 0.75 mg/L and 0.8 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 1 mg/L and 0.6 mg/L.

Typically, where the aerosol comprises meperidine, the delivered aerosolhas an inhalable aerosol drug mass density of between 5 mg/L and 100mg/L. Preferably, the aerosol has an inhalable aerosol drug mass densityof between 7.5 mg/L and 80 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 10 mg/L and 60 mg/L.

Typically, where the aerosol comprises methadone, the delivered aerosolhas an inhalable aerosol drug mass density of between 0.25 mg/L and 20mg/L. Preferably, the aerosol has an inhalable aerosol drug mass densityof between 0.5 mg/L and 17.5 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 0.75 mg/L and 15 mg/L.

Typically, where the aerosol comprises pentazocine, the deliveredaerosol has an inhalable aerosol drug mass density of between 3 mg/L and50 mg/L. Preferably, the aerosol has an inhalable aerosol drug massdensity of between 4 mg/L and 45 mg/L. More preferably, the aerosol hasan inhalable aerosol drug mass density of between 5 mg/L and 40 mg/L.

Typically, the delivered aerosol has an inhalable aerosol particledensity greater than 10⁶ particles/mL. Preferably, the aerosol has aninhalable aerosol particle density greater than 10⁷ particles/mL or 10⁸particles/mL.

Typically, the rate of inhalable aerosol particle formation of thedelivered condensation aerosol is greater than 10⁸ particles per second.Preferably, the aerosol is formed at a rate greater than 10⁹ inhalableparticles per second. More preferably, the aerosol is formed at a rategreater than 10¹⁰ inhalable particles per second.

Typically, the delivered condensation aerosol is formed at a rategreater than 0.5 mg/second. Preferably, the aerosol is formed at a rategreater than 0.75 mg/second. More preferably, the aerosol is formed at arate greater than 1 mg/second, 1.5 mg/second or 2 mg/second.

Typically, where the condensation aerosol comprises morphine, between 5mg and 25 mg of morphine are delivered to the mammal in a singleinspiration. Preferably, between 7.5 mg and 22.5 mg of morphine aredelivered to the mammal in a single inspiration. More preferably,between 10 mg and 20 mg of morphine are delivered in a singleinspiration.

Typically, where the condensation aerosol comprises codeine, between 5mg and 25 mg of codeine are delivered to the mammal in a singleinspiration. Preferably, between 7.5 mg and 22.5 mg of codeine aredelivered to the mammal in a single inspiration. More preferably,between 10 mg and 20 mg of codeine are delivered in a singleinspiration.

Typically, where the condensation aerosol comprises naltrexone, between15 mg and 35 mg of naltrexone are delivered to the mammal in a singleinspiration. Preferably, between 17.5 mg and 32.5 mg of naltrexone aredelivered to the mammal in a single inspiration. More preferably,between 20 mg and 30 mg of naltrexone are delivered in a singleinspiration.

Typically, where the condensation aerosol comprises buprenorphine,between 0.1 mg and 1 mg of buprenorphine are delivered to the mammal ina single inspiration. Preferably, between 0.15 mg and 0.8 mg ofbuprenorphine are delivered to the mammal in a single inspiration. Morepreferably, between 0.2 mg and 0.6 mg of naltrexone are delivered in asingle inspiration.

Typically, where the condensation aerosol comprises fentanyl, between0.01 mg and 0.8 mg of fentanyl are delivered to the mammal in a singleinspiration. Preferably, between 0.02 mg and 0.6 mg of fentanyl aredelivered to the mammal in a single inspiration. More preferably,between 0.03 mg and 0.4 mg of fentanyl are delivered in a singleinspiration.

Typically, where the condensation aerosol comprises nalbuphine, between1 mg and 30 mg of nalbuphine are delivered to the mammal in a singleinspiration. Preferably, between 2 mg and 27.5 mg of nalbuphine aredelivered to the mammal in a single inspiration. More preferably,between 3 mg and 25 mg of nalbuphine are delivered in a singleinspiration.

Typically, where the condensation aerosol comprises naloxone, between0.05 mg and 3.5 mg of naloxone are delivered to the mammal in a singleinspiration. Preferably, between 0.1 mg and 3 mg of naloxone aredelivered to the mammal in a single inspiration. More preferably,between 0.2 mg and 2.5 mg of naloxone are delivered in a singleinspiration.

Typically, where the condensation aerosol comprises butorphanol, between0.1 mg and 3 mg of butorphanol are delivered to the mammal in a singleinspiration. Preferably, between 0.15 mg and 2.75 mg of butorphanol aredelivered to the mammal in a single inspiration. More preferably,between 0.2 mg and 2.5 mg of butorphanol are delivered in a singleinspiration.

Typically, where the condensation aerosol comprises hydromorphone,between 0.1 mg and 10 mg of hydromorphone are delivered to the mammal ina single inspiration. Preferably, between 0.2 mg and 7.5 mg ofhydromorphone are delivered to the mammal in a single inspiration. Morepreferably, between 0.4 mg and 5 mg of hydromorphone are delivered in asingle inspiration.

Typically, where the condensation aerosol comprises oxycodone, between0.5 mg and 10 mg of oxycodone are delivered to the mammal in a singleinspiration. Preferably, between 0.75 mg and 8 mg of oxycodone aredelivered to the mammal in a single inspiration. More preferably,between 1 mg and 6 mg of oxycodonel are delivered in a singleinspiration.

Typically, where the condensation aerosol comprises meperidine, between5 mg and 100 mg of meperidine are delivered to the mammal in a singleinspiration. Preferably, between 7.5 mg and 80 mg of meperidine aredelivered to the mammal in a single inspiration. More preferably,between 10 mg and 60 mg of meperidine are delivered in a singleinspiration.

Typically, where the condensation aerosol comprises methadone, between0.25 mg and 20 mg of methadone are delivered to the mammal in a singleinspiration. Preferably, between 0.5 mg and 17.5 mg of methadone aredelivered to the mammal in a single inspiration. More preferably,between 0.75 mg and 15 mg of methadone are delivered in a singleinspiration.

Typically, where the condensation aerosol comprises pentazocine, between3 mg and 50 mg of pentazocine are delivered to the mammal in a singleinspiration. Preferably, between 4 mg and 45 mg of pentazocine aredelivered to the mammal in a single inspiration. More preferably,between 5 mg and 40 mg of pentazocine are delivered in a singleinspiration.

Typically, the delivered condensation aerosol results in a peak plasmaconcentration of morphine, codeine, naltrexone, buprenorphine, fentanyl,nalbuphine, naloxone, butorphanol, hydromorphone, oxycodone, meperidine,methadone, pentazocine, remifentanil, or sufentanil in the mammal inless than 1 h. Preferably, the peak plasma concentration is reached inless than 0.5 h. More preferably, the peak plasma concentration isreached in less than 0.2, 0.1, 0.05, 0.02, 0.01, or 0.005 h (arterialmeasurement).

In a kit aspect of the present invention, a kit for delivering an opioidthrough an inhalation route to a mammal is provided which comprises: a)a composition comprising at least 5 percent by weight of an opioid; and,b) a device that forms an opioid aerosol from the composition, forinhalation by the mammal. Preferably, the composition comprises at least20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent,80 percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5percent, 99.9 percent or 99.97 percent by weight of an opioid.

Typically, the device contained in the kit comprises: a) an element forheating the opioid composition to form a vapor; b) an element allowingthe vapor to cool to form an aerosol; and, c) an element permitting themammal to inhale the aerosol.

In another kit aspect of the present invention, a kit for deliveringmorphine, codeine, naltrexone, buprenorphine, fentanyl, nalbuphine,naloxone, butorphanol, hydromorphone, oxycodone, meperidine, methadone,pentazocine, remifentanil, or sufentanil through an inhalation route toa mammal is provided which comprises: a) a composition comprising atleast 5 percent by weight of morphine, codeine, naltrexone,buprenorphine, fentanyl, nalbuphine, naloxone, butorphanol,hydromorphone, oxycodone, meperidine, methadone, pentazocine,remifentanil, or sufentanil; and, b) a device that forms a morphine,codeine, naltrexone, buprenorphine, fentanyl, nalbuphine, naloxone,butorphanol, hydromorphone, oxycodone, meperidine, methadone,pentazocine, remifentanil, or sufentanil aerosol from the composition,for inhalation by the mammal. Preferably, the composition comprises atleast 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent,99.5 percent, 99.9 percent or 99.97 percent by weight of morphine,codeine, naltrexone, buprenorphine, fentanyl, nalbuphine, naloxone,butorphanol, hydromorphone, oxycodone, meperidine, methadone,pentazocine, remifentanil, or sufentanil.

Typically, the device contained in the kit comprises: a) an element forheating the morphine, codeine, naltrexone, buprenorphine, fentanyl,nalbuphine, naloxone, butorphanol, hydromorphone, oxycodone, meperidine,methadone, pentazocine, remifentanil, or sufentanil composition to forma vapor; b) an element allowing the vapor to cool to form an aerosol;and, c) an element permitting the mammal to inhale the aerosol.

BRIEF DESCRIPTION OF THE FIGURE

FIG. 1 shows a cross-sectional view of a device used to deliver opioidaerosols to a mammal through an inhalation route.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

“Aerodynamic diameter” of a given particle refers to the diameter of aspherical droplet with a density of 1 g/mL (the density of water) thathas the same settling velocity as the given particle.

“Aerosol” refers to a suspension of solid or liquid particles in a gas.

“Aerosol drug mass density” refers to the mass of opioid per unit volumeof aerosol.

“Aerosol mass density” refers to the mass of particulate matter per unitvolume of aerosol.

“Aerosol particle density” refers to the number of particles per unitvolume of aerosol.

“Amorphous particle” refers to a particle that does not contain morethan 50 percent by weight of a crystalline form. Preferably, theparticle does not contain more than 25 percent by weight of acrystalline form. More preferably, the particle does not contain morethan 10 percent by weight of a crystalline form.

“Buprenorphine” refers to17-(cyclopropylmethyl)-α-(1,1-dimethylethyl)-4,5-epoxy-18,19-dihydro-3-hydroxy-6-methoxy-α-methyl-6,14-ethanomorphinan-7-methanol.

“Buprenorphine degradation product” refers to a compound resulting froma chemical modification of buprenorphine. The modification, for example,can be the result of a thermally or photochemically induced reaction.Such reactions include, without limitation, oxidation and hydrolysis.

“Butorphanol” refers to 17-(cyclobutylmethyl)morphinan-3,14-diol.

“Butorphanol degradation product” refers to a compound resulting from achemical modification of butorphanol. The modification, for example, canbe the result of a thermally or photochemically induced reaction. Suchreactions include, without limitation, oxidation and hydrolysis. Anexample of a degradation product is a compound of molecular formulaC₅H₈O.

“Codeine” refers to7,8-didehydro-4,5-epoxy-3-methoxy-17-methylmorphinan-6-ol.

“Codeine degradation product” refers to a compound resulting from achemical modification of codeine. The modification, for example, can bethe result of a thermally or photochemically induced reaction. Suchreactions include, without limitation, oxidation and hydrolysis.

“Condensation aerosol” refers to an aerosol formed by vaporization of asubstance followed by condensation of the substance into an aerosol.

“Fentanyl” refers toN-phenyl-N-[1-(2-phenylethyl)-4-piperidinyl]propanamide.

“Fentanyl degradation product” refers to a compound resulting from achemical modification of fentanyl. The modification, for example, can bethe result of a thermally or photochemically induced reaction. Suchreactions include, without limitation, oxidation and hydrolysis.

“Hydromorphone” refers to 4,5-epoxy-3-hydroxy-17-methylmorphinan-6-one.

“Hydromorphone degradation product” refers to a compound resulting froma chemical modification of hydromorphone. The modification, for example,can be the result of a thermally or photochemically induced reaction.Such reactions include, without limitation, oxidation and hydrolysis.

“Inhalable aerosol drug mass density” refers to the aerosol drug massdensity produced by an inhalation device and delivered into a typicalpatient tidal volume.

“Inhalable aerosol mass density” refers to the aerosol mass densityproduced by an inhalation device and delivered into a typical patienttidal volume.

“Inhalable aerosol particle density” refers to the aerosol particledensity of particles of size between 100 nm and 5 microns produced by aninhalation device and delivered into a typical patient tidal volume.

“Mass median aerodynamic diameter” or “MMAD” of an aerosol refers to theaerodynamic diameter for which half the particulate mass of the aerosolis contributed by particles with an aerodynamic diameter larger than theMMAD and half by particles with an aerodynamic diameter smaller than theMMAD.

“Meperidine” refers to 1-methyl-4-phenyl-4-piperidinecarboxylic acidethyl ester.

“Meperidine degradation product” refers to a compound resulting from achemical modification of meperidine. The modification, for example, canbe the result of a thermally or photochemically induced reaction. Suchreactions include, without limitation, oxidation and hydrolysis.

“Methadone” refers to 6-dimethylamino-4,4-diphenyl-3-heptanone.

“Methadone degradation product” refers to a compound resulting from achemical modification of methadone. The modification, for example, canbe the result of a thermally or photochemically induced reaction. Suchreactions include, without limitation, oxidation and hydrolysis.

“Morphine” refers to7,8-didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol.

“Morphine degradation product” refers to a compound resulting from achemical modification of morphine. The modification, for example, can bethe result of a thermally or photochemically induced reaction. Suchreactions include, without limitation, oxidation and hydrolysis.

“Nalbuphine” refers to17-(cyclobutylmethyl)-4,5-epoxy-morphinan-3,6,14-triol.

“Nalbuphine degradation product” refers to a compound resulting from achemical modification of nalbuphine. The modification, for example, canbe the result of a thermally or photochemically induced reaction. Suchreactions include, without limitation, oxidation and hydrolysis.

“Naloxone” refers to4,5-epoxy-3,14-dihydroxy-17-(2-propenyl)morphinan-6-one.

“Naloxone degradation product” refers to a compound resulting from achemical modification of naloxone. The modification, for example, can bethe result of a thermally or photochemically induced reaction. Suchreactions include, without limitation, oxidation and hydrolysis.

“Naltrexone” refers to17-(cyclopropylmethyl)-4,5-epoxy-3,14-dihydroxy-morphinan-6-one.

“Naltrexone degradation product” refers to a compound resulting from achemical modification of naltrexone. The modification, for example, canbe the result of a thermally or photochemically induced reaction. Suchreactions include, without limitation, oxidation and hydrolysis.

“Opioid degradation product” refers to a compound resulting from achemical modification of an opioid. The modification, for example, canbe the result of a thermally or photochemically induced reaction. Suchreactions include, without limitation, oxidation and hydrolysis.

“Oxycodone” refers to4,5-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one.

“Oxycodone degradation product” refers to a compound resulting from achemical modification of oxycodone. The modification, for example, canbe the result of a thermally or photochemically induced reaction. Suchreactions include, without limitation, oxidation and hydrolysis.

“Pentazocine” refers to1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(3-methyl-2-butenyl)-2,6-methano-3-benzazocin-8-ol.

“Pentazocine degradation product” refers to a compound resulting from achemical modification of pentazocine. The modification, for example, canbe the result of a thermally or photochemically induced reaction. Suchreactions include, without limitation, oxidation and hydrolysis.

“Rate of aerosol formation” refers to the mass of aerosolizedparticulate matter produced by an inhalation device per unit time.

“Rate of inhalable aerosol particle formation” refers to the number ofparticles of size between 100 nm and 5 microns produced by an inhalationdevice per unit time.

“Rate of drug aerosol formation” refers to the mass of aerosolizedopioid produced by an inhalation device per unit time.

“Remifentanil” refers to3-[4-methoxycarbonyl-4-[(1-oxopropyl)phenylamino]-1-piperidine]propanoicacid methyl ester.

“Remifentanil degradation product” refers to a compound resulting from achemical modification of remifentanil. The modification, for example,can be the result of a thermally or photochemically induced reaction.Such reactions include, without limitation, oxidation and hydrolysis.

“Settling velocity” refers to the terminal velocity of an aerosolparticle undergoing gravitational settling in air.

“Typical patient tidal volume” refers to 1 L for an adult patient and 15mL/kg for a pediatric patient.

“Vapor” refers to a gas, and “vapor phase” refers to a gas phase. Theterm “thermal vapor” refers to a vapor phase, aerosol, or mixture ofaerosol-vapor phases, formed preferably by heating.

Formation of Opioid Containing Aerosols

Any suitable method is used to form the aerosols of the presentinvention. A preferred method, however, involves heating a compositioncomprising an opioid to form a vapor, followed by cooling of the vaporsuch that it condenses to provide an opioid comprising aerosol(condensation aerosol). The composition is heated in one of four forms:as pure active compound (e.g., pure morphine, codeine, naltrexone,buprenorphine, fentanyl, nalbuphine, naloxone, butorphanol,hydromorphone, oxycodone, meperidine, methadone, pentazocine,remifentanil, or sufentanil); as a mixture of active compound and apharmaceutically acceptable excipient; as a salt form of the pure activecompound; and, as a mixture of active compound salt form and apharmaceutically acceptable excipient.

Salt forms of opioids (e.g., morphine, codeine, naltrexone,buprenorphine, fentanyl, nalbuphine, naloxone, butorphanol,hydromorphone, oxycodone, meperidine, methadone, pentazocine,remifentanil, or sufentanil) are either commercially available or areobtained from the corresponding free base using well known methods inthe art. A variety of pharmaceutically acceptable salts are suitable foraerosolization. Such salts include, without limitation, the following:hydrochloric acid, hydrobromic acid, acetic acid, maleic acid, formicacid, and fumaric acid salts.

Pharmaceutically acceptable excipients may be volatile or nonvolatile.Volatile excipients, when heated, are concurrently volatilized,aerosolized and inhaled with the opioid. Classes of such excipients areknown in the art and include, without limitation, gaseous, supercriticalfluid, liquid and solid solvents. The following is a list of exemplarycarriers within the classes: water; terpenes, such as menthol; alcohols,such as ethanol, propylene glycol, glycerol and other similar alcohols;dimethylformamide; dimethylacetamide; wax; supercritical carbon dioxide;dry ice; and mixtures thereof.

Solid supports on which the composition is heated are of a variety ofshapes. Examples of such shapes include, without limitation, cylindersof less than 1.0 mm in diameter, boxes of less than 1.0 mm thickness andvirtually any shape permeated by small (e.g., less than 1.0 mm-sized)pores. Preferably, solid supports provide a large surface to volumeratio (e.g., greater than 100 per meter) and a large surface to massratio (e.g., greater than 1 cm² per gram).

A solid support of one shape can also be transformed into another shapewith different properties. For example, a flat sheet of 0.25 mmthickness has a surface to volume ratio of approximately 8,000 permeter. Rolling the sheet into a hollow cylinder of 1 cm diameterproduces a support that retains the high surface to mass ratio of theoriginal sheet but has a lower surface to volume ratio (about 400 permeter).

A number of different materials are used to construct the solidsupports. Classes of such materials include, without limitation, metals,inorganic materials, carbonaceous materials and polymers. The followingare examples of the material classes: aluminum, silver, gold, stainlesssteel, copper and tungsten; silica, glass, silicon and alumina;graphite, porous carbons, carbon yarns and carbon felts;polytetrafluoroethylene and polyethylene glycol. Combinations ofmaterials and coated variants of materials are used as well.

Where aluminum is used as a solid support, aluminum foil is a suitablematerial. Examples of silica, alumina and silicon based materialsinclude amphorous silica S-5631 (Sigma, St. Louis, Mo.), BCR171 (analumina of defined surface area greater than 2 m²/g from Aldrich, St.Louis, Mo.) and a silicon wafer as used in the semiconductor industry.Carbon yarns and felts are available from American Kynol, Inc., NewYork, N.Y. Chromatography resins such as octadecycl silane chemicallybonded to porous silica are exemplary coated variants of silica.

The heating of the opioid compositions is performed using any suitablemethod. Examples of methods by which heat can be generated include thefollowing: passage of current through an electrical resistance element;absorption of electromagnetic radiation, such as microwave or laserlight; and, exothermic chemical reactions, such as exothermic solvation,hydration of pyrophoric materials and oxidation of combustiblematerials.

Delivery of Opioid Containing Aerosols

Opioid containing aerosols of the present invention are delivered to amammal using an inhalation device. Where the aerosol is a condensationaerosol, the device has at least three elements: an element for heatingan opioid containing composition to form a vapor; an element allowingthe vapor to cool, thereby providing a condensation aerosol; and, anelement permitting the mammal to inhale the aerosol. Various suitableheating methods are described above. The element that allows cooling is,in it simplest form, an inert passageway linking the heating means tothe inhalation means. The element permitting inhalation is an aerosolexit portal that forms a connection between the cooling element and themammal's respiratory system.

One device used to deliver the opioid containing aerosol is described inreference to FIG. 1. Delivery device 100 has a proximal end 102 and adistal end 104, a heating module 106, a power source 108, and amouthpiece 110. An opioid composition is deposited on a surface 112 ofheating module 106. Upon activation of a user activated switch 114,power source 108 initiates heating of heating module 106 (e.g, throughignition of combustible fuel or passage of current through a resistiveheating element). The opioid composition volatilizes due to the heatingof heating module 106 and condenses to form a condensation aerosol priorto reaching the mouthpiece 110 at the proximal end of the device 102.Air flow traveling from the device distal end 104 to the mouthpiece 110carries the condensation aerosol to the mouthpiece 110, where it isinhaled by the mammal.

Devices, if desired, contain a variety of components to facilitate thedelivery of opioid containing aerosols. For instance, the device mayinclude any component known in the art to control the timing of drugaerosolization relative to inhalation (e.g., breath-actuation), toprovide feedback to patients on the rate and/or volume of inhalation, toprevent excessive use (i.e., “lock-out” feature), to prevent use byunauthorized individuals, and/or to record dosing histories.

Dosage of Opioid Containing Aerosols

The dosage amount of an opiod in aerosol form is generally no greaterthan twice the standard dose of the drug given orally. For instance,morphine, codeine, naltrexone, buprenorphine, fentanyl, nalbuphine,naloxone, butorphanol, hydromorphone, oxycodone, meperidine, methadone,and pentazocine, are given at strengths of 15 mg, 15 mg, 25 mg, 0.3 to0.6 mg, 0.1 to 0.4 mg, 10 mg, 0.4 to 2 mg, 0.5 to 2 mg, 2 to 4 mg, 5 mg,50 mg, 2.5 to 10 mg, and 30 mg, respectively for the treatment of pain,alcohol addiction and maintenance of opioid addicts. As aerosols, 5 mgto 25 mg of morphine, 5 mg to 25 mg of codeine, 15 mg to 35 mg ofnaltrexone, 0.1 to 1 mg of buprenorphine, 0.01 to 0.8 mg of fentanyl, 1to 30 mg of nalbuphine, 0.05 to 3.5 mg of naloxone, 0.1 to 3 mg ofbutorphanol, 0.1 to 10 mg of hydromorphone, 0.5 to 10 mg of oxycodone, 5to 100 mg of meperidine, 0.25 to 20 mg of methadone, and 3 to 50 mg ofpentazocine are generally provided for the same indications. A typicaldosage of an opioid aerosol is either administered as a singleinhalation or as a series of inhalations taken within an hour or less(dosage equals sum of inhaled amounts). Where the drug is administeredas a series of inhalations, a different amount may be delivered in eachinhalation.

One can determine the appropriate dose of opioid containing aerosols totreat a particular condition using methods such as animal experimentsand a dose-finding (Phase I/II) clinical trial. One animal experimentinvolves measuring plasma concentrations of drug in an animal after itsexposure to the aerosol. Mammals such as dogs or primates are typicallyused in such studies, since their respiratory systems are similar tothat of a human. Initial dose levels for testing in humans is generallyless than or equal to the dose in the mammal model that resulted inplasma drug levels associated with a therapeutic effect in humans. Doseescalation in humans is then performed, until either an optimaltherapeutic response is obtained or a dose-limiting toxicity isencountered.

Analysis of Opioid Containing Aerosols

Purity of an opioid containing aerosol is determined using a number ofmethods, examples of which are described in Sekine et al., Journal ofForensic Science 32:1271–1280 (1987) and Martin et al., Journal ofAnalytic Toxicology 13:158–162 (1989). One method involves forming theaerosol in a device through which a gas flow (e.g., air flow) ismaintained, generally at a rate between 0.4 and 60 L/min. The gas flowcarries the aerosol into one or more traps. After isolation from thetrap, the aerosol is subjected to an analytical technique, such as gasor liquid chromatography, that permits a determination of compositionpurity.

A variety of different traps are used for aerosol collection. Thefollowing list contains examples of such traps: filters; glass wool;impingers; solvent traps, such as dry ice-cooled ethanol, methanol,acetone and dichloromethane traps at various pH values; syringes thatsample the aerosol; empty, low-pressure (e.g., vacuum) containers intowhich the aerosol is drawn; and, empty containers that fully surroundand enclose the aerosol generating device. Where a solid such as glasswool is used, it is typically extracted with a solvent such as ethanol.The solvent extract is subjected to analysis rather than the solid(i.e., glass wool) itself. Where a syringe or container is used, thecontainer is similarly extracted with a solvent.

The gas or liquid chromatograph discussed above contains a detectionsystem (i.e., detector). Such detection systems are well known in theart and include, for example, flame ionization, photon absorption andmass spectrometry detectors. An advantage of a mass spectrometrydetector is that it can be used to determine the structure of opioiddegradation products.

Particle size distribution of an opioid containing aerosol is determinedusing any suitable method in the art (e.g., cascade impaction). AnAndersen Eight Stage Non-viable Cascade Impactor (Andersen Instruments,Smyrna, Ga.) linked to a furnace tube by a mock throat (USP throat,Andersen Instruments, Smyrna, Ga.) is one system used for cascadeimpaction studies.

Inhalable aerosol mass density is determined, for example, by deliveringa drug-containing aerosol into a confined chamber via an inhalationdevice and measuring the mass collected in the chamber. Typically, theaerosol is drawn into the chamber by having a pressure gradient betweenthe device and the chamber, wherein the chamber is at lower pressurethan the device. The volume of the chamber should approximate the tidalvolume of an inhaling patient.

Inhalable aerosol drug mass density is determined, for example, bydelivering a drug-containing aerosol into a confined chamber via aninhalation device and measuring the amount of active drug compoundcollected in the chamber. Typically, the aerosol is drawn into thechamber by having a pressure gradient between the device and thechamber, wherein the chamber is at lower pressure than the device. Thevolume of the chamber should approximate the tidal volume of an inhalingpatient. The amount of active drug compound collected in the chamber isdetermined by extracting the chamber, conducting chromatographicanalysis of the extract and comparing the results of the chromatographicanalysis to those of a standard containing known amounts of drug.

Inhalable aerosol particle density is determined, for example, bydelivering aerosol phase drug into a confined chamber via an inhalationdevice and measuring the number of particles of given size collected inthe chamber. The number of particles of a given size may be directlymeasured based on the light-scattering properties of the particles.Alternatively, the number of particles of a given size is determined bymeasuring the mass of particles within the given size range andcalculating the number of particles based on the mass as follows: Totalnumber of particles=Sum (from size range 1 to size range N) of number ofparticles in each size range. Number of particles in a given sizerange=Mass in the size range/Mass of a typical particle in the sizerange. Mass of a typical particle in a given size range=π*D³*φ/6, whereD is a typical particle diameter in the size range (generally, the meanboundary MMADs defining the size range) in microns, φ is the particledensity (in g/mL) and mass is given in units of picograms (g⁻¹²).

Rate of inhalable aerosol particle formation is determined, for example,by delivering aerosol phase drug into a confined chamber via aninhalation device. The delivery is for a set period of time (e.g., 3 s),and the number of particles of a given size collected in the chamber isdetermined as outlined above. The rate of particle formation is equal tothe number of 100 nm to 5 micron particles collected divided by theduration of the collection time.

Rate of aerosol formation is determined, for example, by deliveringaerosol phase drug into a confined chamber via an inhalation device. Thedelivery is for a set period of time (e.g., 3 s), and the mass ofparticulate matter collected is determined by weighing the confinedchamber before and after the delivery of the particulate matter. Therate of aerosol formation is equal to the increase in mass in thechamber divided by the duration of the collection time. Alternatively,where a change in mass of the delivery device or component thereof canonly occur through release of the aerosol phase particulate matter, themass of particulate matter may be equated with the mass lost from thedevice or component during the delivery of the aerosol. In this case,the rate of aerosol formation is equal to the decrease in mass of thedevice or component during the delivery event divided by the duration ofthe delivery event.

Rate of drug aerosol formation is determined, for example, by deliveringan opioid containing aerosol into a confined chamber via an inhalationdevice over a set period of time (e.g., 3 s). Where the aerosol is pureopioid, the amount of drug collected in the chamber is measured asdescribed above. The rate of drug aerosol formation is equal to theamount of opioid collected in the chamber divided by the duration of thecollection time. Where the opioid containing aerosol comprises apharmaceutically acceptable excipient, multiplying the rate of aerosolformation by the percentage of opioid in the aerosol provides the rateof drug aerosol formation.

Utility of Opioid Containing Aerosols

The morphine, codeine, fentanyl, nalbuphine, butorphanol, hydromorphone,oxycodone, meperidine, pentazocine, remifentanil, or sufentanilcontaining aerosols of the present invention are typically used to treatpain. Naltrexone and naloxone are typically used to treat alcohol abuseand to provide opioid reversal. Buprenorphine and methadone aretypically used in the maintenance of opioid addicts. Other opioids aregenerally provided for the types of indications listed above.

The following examples are meant to illustrate, rather than limit, thepresent invention.

Morphine sulfate, codeine, naltrexone hydrochloride, buprenorphinehydrochloride, fentanyl citrate, nalbuphine hydrochloride, naloxonehydrochloride, butorphanol tartrate, hydromorphone hydrochloride,oxycodone hydrochloride, meperidine hydrochloride, methadonehydrochloride, and pentazocine are commercially available from Sigma(www.sigma-aldrich.com). Other opioids can be obtained from commercialsources or synthesized using standard methods in the art.

EXAMPLE 1 General Procedure for Obtaining Free Base of a Compound Salt

Approximately 1 g of salt (e.g., mono hydrochloride) is dissolved indeionized water (˜30 mL). Three equivalents of sodium hydroxide (1 NNaOH_(aq)) is added dropwise to the solution, and the pH is checked toensure it is basic. The aqueous solution is extracted four times withdichloromethane (˜50 mL), and the extracts are combined, dried (Na₂SO₄)and filtered. The filtered organic solution is concentrated using arotary evaporator to provide the desired free base. If necessary,purification of the free base is performed using standard methods suchas chromatography or recrystallization.

EXAMPLE 2 General Procedure for Volatilizing Compounds from Halogen Bulb

A solution of drug in approximately 120 μL dichloromethane is coated ona 3.5 cm×7.5 cm piece of aluminum foil (precleaned with acetone). Thedichloromethane is allowed to evaporate. The coated foil is wrappedaround a 300 watt halogen tube (Feit Electric Company, Pico Rivera,Calif.), which is inserted into a glass tube sealed at one end with arubber stopper. Running 90 V of alternating current (driven by linepower controlled by a variac) through the bulb for 3.5–5 s affordsthermal vapor (including aerosol), which is collected on the glass tubewalls. Reverse-phase HPLC analysis with detection by absorption of 225nm light is used to determine the purity of the aerosol. (When desired,the system is flushed through with argon prior to volatilization.) Toobtain higher purity aerosols, one can coat a lesser amount of drug,yielding a thinner film to heat. A linear decrease in film thickness isassociated with a linear decrease in impurities.

The following aerosols were obtained using this procedure: morphine (3.1mg, 100% purity); codeine (1.01 mg, 100% purity); naltrexone (1 mg,97.4% purity); buprenorphine (1.1 mg, 98.7% purity); fentanyl (0.13 mg,100% purity); nalbuphine (0.4 mg, 100% purity); naloxone (1.07 mg,99.24% purity); and, butorphanol (1.38 mg, 97.2% purity).

EXAMPLE 3 Particle Size, Particle Density, and Rate of InhalableParticle Formation of Buprenorphine Aerosol

A solution of 1.5 mg buprenorphine in 100 μL 50/50 mixture ofdichloromethane and methyl ethyl ketone was spread out in a thin layeron the central portion of a 3.5 cm×7 cm sheet of aluminum foil. Thedichloromethane and methyl ethyl ketone mixture were allowed toevaporate. Assuming a drug density of about 1 g/cc, the calculatedthickness of the buprenorphine coating on the 24.5 cm² aluminum solidsupport, after solvent evaporation, is about 0.6 microns. The aluminumfoil was wrapped around a 300 watt halogen tube, which was inserted intoa T-shaped glass tube. Both of the openings of the tube were left openand the third opening was connected to a 1 liter, 3-neck glass flask.The glass flask was further connected to a large piston capable ofdrawing 1.1 liters of air through the flask. Alternating current was runthrough the halogen bulb by application of 90 V using a variac connectedto 110 V line power. Within 1 s, an aerosol appeared and was drawn intothe 1 L flask by use of the piston, with collection of the aerosolterminated after 6 s. The aerosol was analyzed by connecting the 1 Lflask to an eight-stage Andersen non-viable cascade impactor. Resultsare shown in table 1. MMAD of the collected aerosol was 1.1 microns witha geometric standard deviation of 4.2. Also shown in table 1 is thenumber of particles collected on the various stages of the cascadeimpactor, given by the mass collected on the stage divided by the massof a typical particle trapped on that stage. The mass of a singleparticle of diameter D is given by the volume of the particle, πD³/6,multiplied by the density of the drug (taken to be 1 g/cm³). Theinhalable aerosol particle density is the sum of the numbers ofparticles collected on impactor stages 3 to 8 divided by the collectionvolume of 1 L, giving an inhalable aerosol particle density of 7.2×10⁷particles/mL. The rate of inhalable aerosol particle formation is thesum of the numbers of particles collected on impactor stages 3 through 8divided by the formation time of 6 s, giving a rate of inhalable aerosolparticle formation of 1.2×10¹⁰ particles/second.

TABLE 1 Determination of the characteristics of a buprenorphinecondensation aerosol by cascade impaction using an Andersen 8-stagenon-viable cascade impactor run at 1 cubic foot per minute air flow.Mass Particle size Average particle collected Number of Stage range(microns) size (microns) (mg) particles 0  9.0–10.0 9.5 0.01 3.1 × 10⁴ 15.8–9.0 7.4 0.02 1.1 × 10⁵ 2 4.7–5.8 5.25 0.03 4.1 × 10⁵ 3 3.3–4.7 4.00.05 1.5 × 10⁶ 4 2.1–3.3 2.7 0.10 9.7 × 10⁶ 5 1.1–2.1 1.6 0.19 8.9 × 10⁷6 0.7–1.1 0.9 0.08 2.1 × 10⁸ 7 0.4–0.7 0.55 0.03 3.4 × 10⁸ 8   0–0.4 0.20.30  7.2 × 10¹⁰

EXAMPLE 4 Drug Mass Density and Rate of Drug Aerosol Formation ofBuprenorphine Aerosol

A solution of 1.2 mg buprenorphine in 100 μL 50/50 mixture ofdichloromethane and methyl ethyl ketone was spread out in a thin layeron the central portion of a 3.5 cm×7 cm sheet of aluminum foil. Thedichloromethane and methyl ethyl ketone were allowed to evaporate.Assuming a drug density of about 1 g/cc, the calculated thickness of thebuprenorphine coating on the 24.5 cm² aluminum solid support, aftersolvent evaporation, is about 0.5 microns. The aluminum foil was wrappedaround a 300 watt halogen tube, which was inserted into a T-shaped glasstube. Both of the openings of the tube were left open and the thirdopening was connected to a 1 liter, 3-neck glass flask. The glass flaskwas further connected to a large piston capable of drawing 1.1 liters ofair through the flask. Alternating current was run through the halogenbulb by application of 90 V using a variac connected to 110 V linepower. Within seconds, an aerosol appeared and was drawn into the 1 Lflask by use of the piston, with formation of the aerosol terminatedafter 6 s. The aerosol was allowed to sediment onto the walls of the 1 Lflask for approximately 30 minutes. The flask was then extracted withacetonitrile and the extract analyzed by HPLC with detection by lightabsorption at 225 nm. Comparison with standards containing known amountsof buprenorphine revealed that 0.2 mg of> 99% pure buprenorphine hadbeen collected in the flask, resulting in an aerosol drug mass densityof 0.2 mg/L. The aluminum foil upon which the buprenorphine hadpreviously been coated was weighed following the experiment. Of the 1.2mg originally coated on the aluminum, 0.7 mg of the material was foundto have aerosolized in the 6 s time period, implying a rate of drugaerosol formation of 0.1 mg/s.

1. A method of treating pain or alcohol abuse in a patient, or providing opioid reversal therapy or opioid maintenance therapy to a patient comprising administering a therapeutic amount of a drug condensation aerosol to the patient by inhalation, wherein the drug is selected from the group consisting of fentanyl, naltrexone, buprenorphine, naloxone, butorphanol, hydromorphone, oxycodone, methadone, remifentanil and sufentanil, and wherein the condensation aerosol is formed by heating a thin layer containing the drug, on a solid support, to produce a vapor of the drug, and condensing the vapor to form a condensation aerosol characterized by less than 10% drug degradation products by weight, and an MMAD of less than 5 microns.
 2. The method according to claim 1, wherein the condensation aerosol is characterized by an MMAD of less than 3 microns.
 3. The method according to claim 1, wherein peak plasma drug concentration is reached in less than 0.1 hours.
 4. The method according to claim 1, wherein the condensation aerosol is formed at a rate greater than 0.5 mg/second.
 5. The method according to claim 1, wherein at least 50% by weight of the condensation aerosol is amorphous in form.
 6. The method according to claim 1, wherein the therapeutic amount of a drug condensation aerosol comprises between 0.01 mg and 0.8 mg of fentanyl delivered in a single inspiration.
 7. The method according to claim 1, wherein the therapeutic amount of a drug condensation aerosol comprises between 15 mg and 35 mg of naltrexone delivered in a single inspiration.
 8. The method according to claim 1, wherein the therapeutic amount of a drug condensation aerosol comprises between 0.1 mg and 1 mg of buprenorphine delivered in a single inspiration.
 9. The method according to claim 1, wherein the therapeutic amount of a drug condensation aerosol comprises between 0.05 mg and 3.5 mg of naloxone delivered in a single inspiration.
 10. The method according to claim 1, wherein the therapeutic amount of a drug condensation aerosol comprises between 0.1 mg and 3 mg of butorphanol delivered in a single inspiration.
 11. The method according to claim 1, wherein the therapeutic amount of a drug condensation aerosol comprises between 0.1 mg and 10 mg of hydromorphone delivered in a single inspiration.
 12. The method according to claim 1, wherein the therapeutic amount of a drug condensation aerosol comprises between 0.5 mg and 10 mg of oxycodone delivered in a single inspiration.
 13. The method according to claim 1, wherein the therapeutic amount of a drug condensation aerosol comprises between 0.25 mg and 20 mg of methadone delivered in a single inspiration.
 14. A method of administering a drug condensation aerosol to a patient comprising administering the drug condensation aerosol to the patient by inhalation, wherein the drug is selected from the group consisting of fentanyl, naltrexone, buprenorphine, naloxone, butorphanol, hydromorphone, oxycodone, methadone, remifentanil and sufentanil, and wherein the drug condensation aerosol is formed by heating a thin layer containing the drug, on a solid support, to produce a vapor of the drug, and condensing the vapor to form a condensation aerosol characterized by less than 10% drug degradation products by weight, and an MMAD of less than 5 microns.
 15. A kit for delivering a drug condensation aerosol comprising: a. a thin layer containing the drug, on a solid support, wherein the drug is selected from the group consisting of fentanyl, naltrexone, buprenorphine, naloxone, butorphanol, hydromorphone, oxycodone, methadone, remifentanil and sufentanil, and b. a device for providing the condensation aerosol, wherein the condensation aerosol is formed by heating the thin layer to produce a vapor of the drug, and condensing the vapor to form a condensation aerosol characterized by less than 10% drug degradation products by weight, and an MMAD of less than 5 microns.
 16. The kit according to claim 15, wherein the device comprises: a. a flow through enclosure containing the solid support, b. a power source that can be activated to heat the solid support, and c. at least one portal through which air can be drawn by inhalation, wherein activation of the power source is effective to produce a vapor of the drug, and drawing air through the enclosure is effective to condense the vapor to form the condensation aerosol.
 17. The kit according to claim 16, wherein the heat for heating the solid support is generated by an exothermic chemical reaction.
 18. The kit according to claim 17, wherein the exothermic chemical reaction is oxidation of combustible materials.
 19. The kit according to claim 16, wherein the heat for heating the solid support is generated by passage of current through an electrical resistance element.
 20. The kit according to claim 16, wherein the solid support has a surface area dimensioned to accommodate a therapeutic dose of the drug.
 21. The kit according to claim 15, wherein peak plasma drug concentration is reached in less than 0.1 hours.
 22. The kit according to claim 15, further including instructions for use.
 23. The method according to claim 1, wherein the condensation aerosol is characterized by an MMAD of 0.1 to 5 microns.
 24. The method according to claim 1, wherein the condensation aerosol is characterized by an MMAD of about 0.2 to about 3 microns.
 25. The method according to claim 14, wherein the drug is fentanyl.
 26. The method according to claim 14, wherein the drug is naltrexone.
 27. The method according to claim 14, wherein the drug is buprenorphine.
 28. The method according to claim 14, wherein the drug is naloxone.
 29. The method according to claim 14, wherein the drug is butorphanol.
 30. The method according to claim 14, wherein the drug is hydromorphone.
 31. The method according to claim 14, wherein the drug is oxycodone.
 32. The method according to claim 14, wherein the drug is methadone.
 33. The method according to claim 14, wherein the drug is remifentanil.
 34. The method according to claim 14, wherein the drug is sufentanil.
 35. The kit according to claim 15, wherein the condensation aerosol is characterized by an MMAD of less than 3 microns.
 36. The kit according to claim 15, wherein the condensation aerosol is characterized by an MMAD of 0.1 to 5 microns.
 37. The kit according to claim 15, wherein the condensation aerosol is characterized by an MMAD of about 0.2 to about 3 microns.
 38. The kit according to claim 15, wherein the drug is fentanyl.
 39. The kit according to claim 15, wherein the drug is naltrexone.
 40. The kit according to claim 15, wherein the drug is buprenorphine.
 41. The kit according to claim 15, wherein the drug is naloxone.
 42. The kit according to claim 15, wherein the drug is butorphanol.
 43. The kit according to claim 15, wherein the drug is hydromorphone.
 44. The kit according to claim 15, wherein the drug is oxycodone.
 45. The kit according to claim 15, wherein the drug is methadone.
 46. The kit according to claim 15, wherein the drug is remifentanil.
 47. The kit according to claim 15, wherein the drug is sufentanil.
 48. The kit according to claim 16, wherein the solid support has a surface to mass ratio of greater than 1 cm² per gram.
 49. The kit according to claim 16, wherein the solid support has a surface to volume ratio of greater than 100 per meter.
 50. The kit according to claim 16, wherein the solid support is a metal foil.
 51. The kit according to claim 50, wherein the metal foil has a thickness of less than 0.25 mm. 